Spin Traps and Spin Labels for the Treatment of Rectal Hemorrhoids

ABSTRACT

Nitrone, nitroso, and nitroxide spintraps and spin labels and their reduction products are claimed for the treatment of rectal hemorrhoids and rectal fissures.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent application Ser. No. 12/941,071, filed Nov. 7, 2010, which claims the benefit of U.S. Provisional Application No. 6125913, filed Nov. 7, 2009, which are expressly incorporated by reference in their entireties.

This is a Continuation in Part of application Ser. No. 12/941,071, filed Nov. 17, 2010.

BACKGROUND OF THE INVENTION

(1) Field of Invention

Treatment of Rectal Hemorrhoids

(2) Description of Related Art

CITATIONS

Cuscela, Daniel, et al. “Protection from Radiation-Induced Alopecia with Topical Application of Nitroxides: Fractionated Studies”, The Cancer Journal from Scientific American, 1996; vol. 2, No. 5, pp. 273-278.

Proctor P H. Uric acid and neuroprotection. Stroke. 2008 August; 39(8):e126.

Augusto O, Trindade D F, Linares E, Vaz S M. Cyclic nitroxides inhibit the toxicity of nitric oxide-derived oxidants: mechanisms and implications. An Acad Bras Cienc. 2008 March; 80(1):179-89.

Wilcox C S, Pearlman A. Chemistry and antihypertensive effects of tempol and other nitroxides. Pharmacol Rev. 2008 December; 60(4):418-69.

Simonsen U, Christensen F H, Buus N H. The effect of tempol on endothelium-dependent vasodilatation and blood pressure. Pharmacol Ther. 2009 May; 122(2):109-24.

Kamat C D, Gadal S, Mhatre M, Williamson K S, Pye Q N, Hensley K. Antioxidants in central nervous system diseases: preclinical promise and translational challenges. J Alzheimers Dis. 2008 November; 15(3):473-93.

Floyd R A. Serendipitous findings while researching oxygen free radicals. Free Radic Biol Med. 2009 Apr. 15; 46(8):1004-13.

Schubert M C, Sridhar S, Schade R R, Wexner S D. What every gastroenterologist needs to know about common anorectal disorders. World J Gastroenterol. 2009 Jul. 14; 15(26):3201-9. Review.

Varut Lohsiriwat, Hemorrhoids: From basic pathophysiology to clinical management, World J Gastroenterol. 2012:18(17): 2009-2017.

Wilcox C S. Effects of tempol and redox-cycling nitroxides in models of oxidative stress. Pharmacol Ther. 2010 May; 126(2):119-45.

Traystman R J. Neuroprotection: introduction. Stroke. 2010 October; 41(10 Suppl):S63

FIELD OF THE INVENTION

The present invention is directed to methods that treat, inhibit, or slow the development of rectal hemorrhoids The inventive methods comprise the administration of pharmaceutical preparations comprising nitrone, nitroxide and nitroso compounds and their corresponding reduction products orally, intraorally, systemically by injection, and by local rectal administration.

BACKGROUND OF THE INVENTION

Various publications, including patents, published applications, and scholarly or technical articles are cited above and throughout the specification. Each of the cited publications is incorporated by reference herein, in its entirety.

DESCRIPTION

Often described as “varicose veins of the anus and rectum”, rectal hemorrhoids are enlarged, bulging blood vessels in and about the anus and lower rectum. There are two types of hemorrhoids: external and internal, which refer to their location. External (outside) hemorrhoids develop near the anus and are covered by very sensitive skin. These are usually painless. However, if a blood clot (thrombosis) develops in an external hemorrhoid, it becomes a painful, hard lump. The external hemorrhoid may bleed if it ruptures. Internal (inside) hemorrhoids develop within the anus beneath the lining. Painless bleeding and protrusion during bowel movements are the most common symptom. However, an internal hemorrhoid can cause severe pain if it is completely “prolapsed”—protrudes from the anal opening and cannot be pushed back inside.

The exact cause of rectal hemorrhoids and related rectal fissures is unknown; however, the upright posture of humans alone forces a great deal of pressure on the rectal veins, which sometimes causes them to bulge. Other contributing factors in both rectal hemorrhoids and fissures include: aging, chronic constipation or diarrhea, pregnancy, heredity, straining during bowel movements, and faulty bowel function due to overuse of laxatives or enemas.

Whatever the cause, the tissues supporting the vessels stretch. As a result, the vessels dilate; their walls become thin and bleed. If the stretching and pressure continue, the weakened vessels protrude. Symptomes of rectal hemorrhoids include bleeding during bowel movements, protrusion during bowel movements, itching in the anal area, pain, and sensitive lump(s). (Varut Lohsiriwat, Hemorrhoids: From basic pathophysiology to clinical management, World J Gastroenterol. 2012:18(17): 2009-2017.) Treatment is mainly surgical and/or analgesics an antiinflammatory agents.

The efficacy of various nitrone, nitroso, and nitroxide spin traps and spin labels and their equivalent reduction products in some model diseases in experimental animals has long been recognized. However, studies with such antioxidant drugs have not well translated to humans. E.g., with respect to neuroprotection in general and nitrone and nitroxide drugs in particular: “There are hundreds, perhaps thousands of neuroprotective drugs that have been used in animal models. So, if you were a mouse or a rat, and experienced a stroke or cardiac arrest, we would know just what to do for you. But, essentially none of these pharmacological agents have demonstrated usefulness in humans even though they have been shown to be successful in preclinical animal trials” (Traystman R J. Neuroprotection: introduction. Stroke. 2010 October; 41(10 Suppl):S63.). In particular, one such neuroprotective agent effective in animal models, but not in humans, is the phenybutylnitrone derivative NXY-059.

Moreover, in animals treatment effects are reported at systemic human equivalent doses orders of magnitude higher than we found efficacy in (e.g.) fibrocystic disease in humans.

If the in vivo active form is (say) the reduced derivative, this may be an unexpected consequence of the presence in humans and higher primates of singularly high levels of the powerful reducing substance uric acid. Paradoxically, since it competes with them for action, the singularly-high level of urate in humans may also may explain the perpetual failure of antioxidant drugs such as NXY-059 (the disulfonyl derivative of PBN) in human clinical trials, even at several grams per day doses (Proctor P H. Uric acid and neuroprotection. Stroke. 2008 August; 39(8):e126.). That is, any efficacy of such nitrone, nitroso, and nitroxide drugs in humans, much less efficacy at very low doses, is unexpected.

Similarly, we recognized the potential benefit of administering such compounds topically in their reduced forms (5714482, 5714510, 5716947, 5723502, 5728714), e.g., in presence of a strong reducing compound such as ascorbic acid. For one thing, coadministration in the reduced form or in the presence of a reducing substances may prevent depletion of endogenous reducing equivalents by the parent drugs and thus induce oxidative stress.

These patents are here-by incorporated by reference. However, the efficacy, much less the benefits, of the using such reduced forms is disputed. E.g., Hsia et al (U.S. Pat. No. 7,314,633) note that “If a nitroxide is reduced to a hydroxylamine it loses its ability to modulate reactions. By positioning the nitroxide between two carboxylic acid groups a “gating” effect is obtained, i.e. the nitroxide is protected and its ability to modulate reactions is maintained over a longer period of time in a greater range of in vivo environments as compared to a molecule lacking the carboxylic acid groups.”

Moreover, because there is no good animal model for rectal hemmorrhoids, such agents have never been considered for the treatment of this condition. That is, for lack of animal models, recognition of the efficacy of such compounds had to await the use of such compounds in persons with the actual human disease. In fact, previously, the only human use of (e.g.) TEMPOL was experimental topical treatment to ameliorate radiation injury (Wilcox, 2010).

However, in the course of extemporaneous treatment with an oral formulation of the reduced form of TEMPOL (TEMPOL-H), we unexpectedly observed and documented regression of long-standing and recurrent rectal hemorrhoids.

DEFINITIONS

The term “nitroxide”, “nitrone”, and “nitroso” are used herein to describe molecules comprising an oxygen and a nitrogen atom directly bound to each other. These compounds may be a electron donors or acceptors. Depending on their oxidation state, these compounds may comprise stable nitroxyl free radicals including precursors (such as the N—H form), and derivatives thereof including their corresponding hydroxylamine derivative (N—OH), where the oxygen atoms are replaced with a hydroxyl group and/or exist in a hydrogen halide form. The Nitroxide radicals and their hypdroxylamines of the invention may be administered to a system, such as a human, and act to modulate oxidation and reduction reactions by donating or accepting an electron. Other mechanisms may include formation of charge-transfer complexes as well as by “redox signaling” or modulation of redox-signaling-mediated processes. Stability of unpaired electrons on such compounds is typically-provided at the nitrogen nucleus by two adjacent carbon atoms that may be substituted with strong electron donor groups. With the partial negative charge on the oxygen of the N—O bond, the two adjacent carbon atoms together localize the unpaired electron on the nitrogen nucleus. Redox-cycling Nitroxides generally may have either a heterocyclic or a linear structure. In an vivo environment a nitroxide may react with a first superoxide to form oxoammonium (as an electron donor) and then react with a second superoxide to re-form the nitroxide (as an electron acceptor). (Review, incorporated by reference: Wilcox C S. Effects of tempol and redox-cycling nitroxides in models of oxidative stress. Pharmacol Ther. 2010 May; 126(2):119-45.)

The terms “treat,” “treatment” and the like are used herein to generally mean obtaining a desired pharmacological and/or physiological effect in humans or other animals. A treatment is an approach for obtaining beneficial or desired clinical results. While the claims are not dependent on any specific mechanism, in the present case, these clinical results include but are not limited to decreasing undesirable effects of reactive oxygen species (ROS) and oxidative stress in general, as well as modulating more specific messenger processes such as “redox signaling”. The effect may be prophylactic in terms of completely or partially preventing a disease and/or symptom thereof and/or may be therapeutic in terms of a partial or complete cure of the disease and/or adverse effect attributed to the disease. In general, methods of the invention may be applied to a variety of different areas including the skin, mucus membranes including those in the GI tract, nose, throat, mouth, vaginal cavity, ocular surfaces, as well as the surfaces of the lungs and the surfaces of the vascular system as well as systemically by means of intravenous, intraocular, intramuscular, transdermal, sublingual, and/or intraoral administration.

“Treatment” as used herein covers any treatment of such a symptom or disease in a mammal, particularly a human, and includes:

(a) preventing or diagnosing the disease and/or symptoms in the subject which may be predisposed to the disease and/or symptom but has not yet been diagnosed as having it;

(b) inhibiting the disease, i.e. arresting it's development; and/or

(c) relieving the disease and/or it's symptom, i.e. causing regression of the disease and/or the symptoms caused by the disease.

Exemplar nitroxide-nitroxide radical spin labels include, but are not limited to, DEPMPO (5-(Diethoxyphosphoryl)-5-methyl-1-pyrroline N-oxide), TEMPO (2,2,6,6-tetramethyl-1-piperidinyl-1-oxyl), 4-Amino-TEMPO, 4-hydroxy-TEMPO (TEMPOL), DMPO (5,5-dimethylpyrroline-N-oxide), EMPO (2-Ethoxycarbonyl-2-methyl-3,4-dihydro-2H-pyrrole-1-oxide), POBN (alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone), TEMPONE (4-Oxo-2,2,6,6-tetramethylpiperidine-1-oxyl 4-Oxo-TEMPO), TMIO ,3,3,5,5 tetramethyl-1-pyrolline-N-oxide (TMPO), M3PO (2,5,5-trimethyl-1-pyrroline-N-oxide), M4PO (3,3,5,5-tetramethyl-1-pyrroline-N-oxide), TMPO (3,3,5,5 tetramethyl-1-pyrolline-N-oxide), PBN (1-alpha-phenyl-tert-butyl nitrone), and the PBN breakdown product MNP (2-methyl-2-nitrosopropane), as well as their corresponding hydroxylamine derivatives. The various sulfone, hydroxyl, esters, peptides, hydroxyl, hydroxylamines, and nitrone derivatives are also claimed.

Preferred examples of the type of hydroxylamine compounds suitable for use in the present invention are TEMPOL-H ((the hydroxylamine reduced form of the nitroxide 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-yloxy), TEMPO-H (the hydroxylamine reduced form of the nitroxide 2,2,6,6-tetramethylpiperidin-1-yloxy) and OXANO-H (2-ethyl-2,4,4-trimethyloxazolidine, which is the reduced form of oxano, 2-ethyl-2,4,4-trimethyloxazolidin-3-yloxy). Other hydroxylamine compounds suitable for use in the present invention include, but are not limited to, those disclosed by Hahn et al. (1998, supra; 2000, supra), Samuni et al. (2001, supra); and in U.S. Pat. No. 5,981,548 to Paolini, et al. (disclosing certain N-hydroxylpiperidine esters and their use as antioxidants in a number of contexts); U.S. Pat. No. 4,404,302 to Gupta et al. (disclosing the use of certain N-hydroxylamines as light stabilizers in plastics formulations); U.S. Pat. No. 5,462,946 to Mitchell et al. (disclosing certain nitroxides deriving from substituted oxazolidines for protection of organisms from oxidative stress); U.S. Pat. No. 3,936,456 to Ramey et al. (disclosing substituted piperazine dione oxyls and hydroxides for the stabilization of polymers); U.S. Pat. No. 4,691,015, to Behrens et al. (describing hydroxylamines derived from hindered amines and the use of certain of them for the stabilization of polyolefins); and the hydroxylamine compounds disclosed in the several aforementioned U.S. patents to Hsia et al. Most of the above-referenced compounds have not been known heretofore for administration to humans. Certainly, none of them has been known for use in the treatment of PMS.

Suitable reducing agents include, but are not limited to: ascorbic acid, lipoic acid, cystine and derivatives such as acetylcysteine, uric acid and other oxyxanthines, methionine, homocysteine, NADPH, NADH, and so forth.

EXAMPLES Treatment of Rectal Hemorrhoids with TEMPOL

Prepare:

5 grams methyl cellulose

100 ml water

Boil until methycellulose dissolves (5-10 minutes)

Alternative is I million-dalton MW 1% propylcellulose, which dissolves overnight without boiling.

Add 5 grams TEMPOL Or Phenylbutylnitrone (PBN) with stirring

Allow to gel.

0.2 ml of this 5% solution of TEMPOL or the appropriate reduced form administered trans- or peri-rectally for one to three days ameliorates the symptoms of rectal hemorrhoids especially pain, swelling, and bleeding.

Treatment of Rectal hemorrhoids With a Spin Trap

Prepare:

5 grams methyl cellulose

100 ml water

Boil until methycellulose dissolves (5-10 minutes)

Alternative is I million-dalton MW 1% propylcellulose, which dissolves overnight without boiling.

Add 5 grams Phenylbutylnitrone (PBN) with stirring.

Allow to gel.

0.2 ml of this 5% solution of PBN or the appropriate reduced form administered trans- or peri-rectally for one to three days ameliorates the symptoms of hemorrhoids, especially pain, swelling, and bleeding.

Alternate forms of oral administration such as tablets, pills or capsules are also effective.

Parental modes of administration such as intravenous, intramuscular, subcutaneous, intraperitoneal, transrectal and so forth are also possible, as are topical modes of administration such as in lotions, creams, gels, and topically-compatible suspensions and solutions. Tempol-H itself is effective at the same doses, as is a 1% formulation of the spintrap phenylbutylnitrone. TEMPOL-H or the equivalent hydroxyamine derivative of other nitroxyl spin labels can be produced by the reaction of TEMPOL or the alternative nitroxyl free radical with a molar excess of a strong reducing substance such as ascorbate, ascorbylpalmitate or other ascorbate ester, as well as other reducing substances listed in the incorporated references.

The proper dosage, optimal number of times to administer the compound (daily, weekly, etc.), and length time in which the parent compounds and/or their hydroxylamines must be administered to the subject as part of a follow-up regimen will be empirically determined by methods that are routine in the art, and may vary with the needs of individual subjects.

The present invention is not limited to the embodiments described and exemplified above, but is capable of variation and modification within the scope of the appended claims.

Also, the claims are not bound by any suggested possible mechanism of action and are independent thereof.

Those skilled in the art will appreciate that numerous changes and modifications can be made to the preferred embodiments of the invention and that such changes and modifications can be made without departing from the spirit of the invention. It is, therefore, intended that the appended claims cover all such equivalent variations as fall within the true spirit and scope of the invention. 

What is claimed is:
 1. A method for the treatment of rectal hemorrhoids or rectal fissures with a spin trap or a spin label.
 2. A method comprising treatment of rectal hemorrhoids or rectal fissures where the spin label is TEMPO or a pharmacologically-active derivative including 4-hydroxy-TEMPO (TEMPOL), 4 aminotempol, (2,2,6,6-tetramethyl-1-piperidinyl-1-oxyl), (2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride monhydrte (Mito TEMPOL) and/or their reduced derivatives TEMPO-H, TEMPOL-H, or mito-TEMPOL-H, as well as their pharmacologically-active esters, amides and ethers.
 3. A method for the treatment of the above where the nitroxide, nitrone, or nitroso compound is phenylbutylnitrone, or its hydrolysis product, 2-methyl, 2-nitrosopropane.
 4. A method comprising treatment of rectal hemorrhoids and rectal fissures where the pharmacologically-effective dose is 0.01-1000 mg per day of a pharmacologically-active nitroxide spin-trap or spin label or their equivalent hydroxylamine or other reduced derivatives administered by suitable means such as orally, sublingually, transrectally, intramuscularly, intravenously, or subcutaneously. 